IMPAKT Study: Imaging Modalities in Pediatric Assessments of Kidney Transplants

项目摘要/摘要 这项提议的首要目标是调查新的定量磁共振成像和超声 影像参数可以可靠地检测肾移植损伤，提示儿童同种异体移植失败的风险。 患有终末期肾病(ESKD)的儿童的死亡率是非终末期肾病儿童的30倍。AS 与透析相比，肾移植提供了显著的生存优势，患有ESKD的儿童经常需要 多个同种异体肾移植的患者。每一次移植都会增加外科、免疫学和致癌性 风险。肾移植损伤是由炎性、感染性、血管和纤维化改变引起的，这些改变可以 最终导致同种异体移植失败。促进同种异体移植物长期存活的一个主要限制是缺乏非 侵入性诊断和预后生物标记物可靠地检测同种异体移植物的早期损伤。这项提议旨在 开发磁共振成像(MRI)和对比增强超声(CEUS)生物标志物以 测量儿童肾移植的炎症反应。目前，肾移植活组织检查是治疗 诊断这种变化，但是侵入性的，并不是没有并发症，这限制了它的使用。确定这样的 标记物将允许我们实施个性化的干预措施，以提高同种异体移植物的存活率并减少 不必要的活组织检查。AIM 1将确定高级MRI和CEUS参数，这些参数与 组织病理学总炎症、Banff评分和慢性移植物损伤指数(CADI)评分。目标2将 确定可预测儿童肾移植受者EGFR变化的MRI和CEUS新参数 移植后6~24个月。这一结果将为新的非侵入性成像生物标志物领域提供信息 在儿童肾移植中。作为此次调查的补充，我计划在1)中接受进一步培训 常规和CEUS研究图像采集和分析，2)MRI研究数据采集和分析 分析，3)基于生物医学成像的以患者为中心的研究研究的设计和实施，以及4) 在严格的研究环境中通过专业发展计划获得领导技能 费城儿童医院和宾夕法尼亚大学。为了实现这些目标，我召集了 以患者为中心的临床肾病研究的多学科专家指导/咨询团队(初级 Mentor，Susan Furth，医学博士)，MRI临床和翻译研究(Timothy Roberts，医学博士； Suraj Serai，博士)，CEU(Chandra Seghal，博士；Susan Back，医学博士；Anush Sridharan，博士)，儿童肾脏 移植生物标记物(Sandra Amaral，MD，MHS)，多国合作网络(Gregory Tasian， 医学博士)、肾脏疾病统计方法(Jarcy Zee博士)和以患者为导向的影像研究(Kassa Darge医学博士；Erum Hartung医学硕士；Hansel Otero医学博士)。拟议的研究，以及 构成我职业发展计划的结构化指导、课程作业和培训将为我提供 确保我作为一名拥有独特技能的独立调查员取得成功所需的技能和经验 开发肾移植的成像生物标记物。

PROJECT SUMMARY/ ABSTRACT The overarching objectives of this proposal are to investigate whether novel quantitative MRI and ultrasound imaging parameters can reliably detect kidney transplant injury that indicates risk of allograft failure in children. Children with end-stage kidney disease (ESKD) have a mortality rate 30 times higher than children without it. As kidney transplantation provides a significant survival advantage over dialysis, children with ESKD often require multiple kidney allografts over their lifespan. Each transplant increases surgical, immunological, and oncogenic risk. Kidney allograft injury results from inflammatory, infectious, vascular, and fibrotic changes that can ultimately result in allograft failure. A major limitation to promoting long-term allograft survival is the lack of non- invasive diagnostic and prognostic biomarkers to reliably detect early injury in the allograft. This proposal seeks to develop magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) biomarkers to measure inflammation of kidney transplant in children. Currently, kidney allograft biopsy is the gold standard to diagnose such changes, but is invasive and not free of complications, which limits its use. Identifying such markers will allow us to implement individualized interventions to improve allograft survival and decrease unnecessary biopsies. Aim 1 will determine advanced MRI and CEUS parameters that associate with histopathological total inflammation Banff score and Chronic Allograft Damage Index (CADI) score. Aim 2 will identify novel MRI and CEUS parameters that predict change of eGFR in pediatric kidney transplant recipients at 6-24 months post-transplantation. The results will inform the field of novel non-invasive imaging biomarkers in pediatric kidney transplantation. Complementary to this investigation I plan to acquire further training in 1) conventional and CEUS research imaging acquisition and analysis, 2) MRI research data acquisition and analysis, 3) design and implementation of biomedical imaging based patient-oriented research studies, and 4) acquire leadership skills through a professional development plan in the rigorous research environment of Children’s Hospital of Philadelphia and University of Pennsylvania. To accomplish these goals, I have assembled a multi-disciplinary mentoring/advisory team of experts in clinical nephrology patient-oriented research (Primary mentor, Susan Furth, MD, PhD), MRI clinical and translational research studies (Timothy Roberts, MD, PhD; Suraj Serai, PhD), CEUS (Chandra Seghal, PhD; Susan Back, MD; Anush Sridharan, PhD), pediatric kidney transplantation biomarkers (Sandra Amaral, MD, MHS), multinational collaborative networks (Gregory Tasian, MD, MSCE), kidney disease statistical methods (Jarcy Zee, PhD), and patient-oriented imaging research (Kassa Darge, MD, PhD; Erum Hartung, MD, MSTR; Hansel Otero, MD). The proposed research, along with the structured mentoring, coursework, and training that comprise my career development plan, will provide me with the skills and experience necessary to ensure my success as an independent investigator with a unique skill set in developing imaging biomarkers for kidney transplantation.